Estrogens have been shown to modulate growth, phenotype, and connectivity of neurons of the developing rodent and human basal forebrain and hippocampus. This ability to alter neuronal morphology and connectivity is retained in certain regions of the adult brain. Recent reports have suggested that the incidence of AD in estrogen replaced postmenopausal women is much lower than in women not given this treatment. How might estrogen treatment alter the expression of AD? Since the work of this ADC has implicated genetic causes of the disease, it seems reasonable to suggest that estrogen treatment might protect neurons from pathological changes associated with the AD genotypes, or exert trophic effects which reverse the AD-related changes. This proposal will further investigate the hypothesis that exposure of the aged (or AD) brain to neurotrophic effects of estrogens results in regenerative (or protective) effects on the functional activity of particular brain neuronal systems. If estrogen exposure promotes neurite outgrowth and remodels neuronal connectivity, it might influence the expression of genes encoding proteins important in growth and synaptogenesis. We propose to examine estrogens effects on expression of a subset of these including Synapse Associated Protein (SNAP-25), Microtubule Associated Protein 2 (MAP-2, a dendritic marker), Tau (a component of the microtubule apparatus and neurofibrillary tangles) and neuromodulin (GAP-43, associated with the neuronal growth cone). We have established that GAP-43 mRNA expression is responsive to estrogen in both the developing and adult basal forebrain. We will examine estrogen's effects on neurons in three different regions of the aged female rat brain. (1) Neurotrophic Effects in Classical Estrogen Target Neurons: Can gonadal steroids restore neuronal function in the bed nucleus of the stria terminalis and medial preoptic area of the aged female rat (as previously seen in male rats)? Estrogen's effects on GAP-43, tau~ SNAP-25, and MAP2 in phenotypically identified neurons will also be examined. (2) Trophic Effects of Estrogen on Basal Forebrain Cholinergic Neurons: Does estrogen treatment of aged female rats enhance choline acetytransferase activity and mRNA in medial septal-basal forebrain system? We will also examine the direct effects of estrogen on cholinergic neurons using co- localization techniques. To relate these studies to possible effects of estrogens in AD brain, we will carry out similar studies in human basal forebrain brain tissue from AD and control subjects available through the ADC autopsy core. If estrogen receptors are present in cholinergic neurons, we will also assess differences in the degree of co-localization from individuals with AD associated with differing genetic backgrounds. (3) Restorative effects in non-classical estrogen responsive neuronal populations of the striatum. Although few estrogen receptors are present in the striatum, estrogen treatment enhances dopaminergic transmission in this structure and improves striatally-dependent motor behaviors. We will examine trophic effects of estrogen in aged rat striatum, and relate these effects to postsynaptic responses to antipsychotic drugs commonly administered to AD patients. These studies will provide new information at the molecular and cellular level about neurotrophic effects of estrogens in the aged brain. This may aid our understanding of protective effects of estrogens.